Iron is essential for cell growth and proliferation due to its role as prosthetic group in proteins required for DNA synthesis and energy metabolism. In humans, cellular iron overload can result in diabetes mellitus and neurodegenerative disease, and is associated with an increased risk of cancer, while iron deficiency perinatally or postnatally can cause neurocognitive impairment, and deficiency in adults cause anemia. All organisms have therefore developed mechanisms to sense, acquire and store iron. In vertebrates, iron metabolism is controlled by iron-regulatory protein 2 (IRP2). IRP2 is a RNA-binding protein that binds to iron-responsive elements (IREs) located in mRNAs of proteins involved in iron uptake, sequestration and export. IRP2 binding to IREs regulates the translation or stability of mRNAs. IRP2 deficiency in mice impairs iron homeostasis in multiple tissues, and leads to hematological, neurodegenerative and metabolic disorders. We have identified novel pathways and proteins regulating IRP2 function: iron-dependent proteolysis by an iron-regulated FBXL5 ubiquitin ligase and iron-independent regulation of RNA-binding activity by cyclin-dependent kinase 1 (CDK1) phosphorylation during the cell cycle. Our goals are to determine how iron regulates IRP2 stability and how IRP2 phosphorylation regulates cell cycle progression. PUBLIC HEALTH RELEVANCE: Millions of patients suffer from diseases involving iron overload and deficiency. The nutritional requirement for iron is due to its role such essential cellular processes as cell division and energy production. Iron dysregulation leads to hematological, metabolic and neurodegenerative diseases, and increases the risk of cancer. Because of the adverse impact of iron disorders on health, understanding how cells and tissues respond to iron overload and deficiency is important for treating these disorders. Iron regulatory protein 2 (IRP2) is a key regulator of cellular iron metabolism. We have discovered two novel mechanisms that regulate IRP2 in proliferating cells and in iron overloaded cells. Increased knowledge of the mechanism by which IRP2 regulates iron balance and cell proliferation is important for developing therapeutics that can be used to target cancer cells and treat iron disorders.